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HSD3B1 genotype identifies glucocorticoid responsiveness in severe asthma.


ABSTRACT: Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. HSD3B1 encodes for 3?-hydroxysteroid dehydrogenase-1 (3?-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive HSD3B1(1245A) allele limits conversion, whereas the adrenal permissive HSD3B1(1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEV1PP). HSD3B1(1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEV1PP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined (n = 318). Validation was performed in a second cohort (SARP I&II; n = 184). DHEA-sulfate is associated with FEV1PP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEV1PP compared with noGC patients (54.3% vs. 75.1%; P < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEV1PP difference in GC vs. noGC patients (73.4% vs. 78.9%; P = 0.39). Results were independently confirmed: FEV1PP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 (P < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 (P = 0.92). The adrenal restrictive HSD3B1(1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3?-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.

SUBMITTER: Zein J 

PROVIDER: S-EPMC6995013 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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<i>HSD3B1</i> genotype identifies glucocorticoid responsiveness in severe asthma.

Zein Joe J   Gaston Benjamin B   Bazeley Peter P   DeBoer Mark D MD   Igo Robert P RP   Bleecker Eugene R ER   Meyers Deborah D   Comhair Suzy S   Marozkina Nadzeya V NV   Cotton Calvin C   Patel Mona M   Alyamani Mohammad M   Xu Weiling W   Busse William W WW   Calhoun William J WJ   Ortega Victor V   Hawkins Gregory A GA   Castro Mario M   Chung Kian Fan KF   Fahy John V JV   Fitzpatrick Anne M AM   Israel Elliot E   Jarjour Nizar N NN   Levy Bruce B   Mauger David T DT   Moore Wendy C WC   Noel Patricia P   Peters Stephen P SP   Teague W Gerald WG   Wenzel Sally E SE   Erzurum Serpil C SC   Sharifi Nima N  

Proceedings of the National Academy of Sciences of the United States of America 20200113 4


Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. <i>HSD3B1</i> encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive <i>HSD3B1</i>(1245A) allele limits conversion, wher  ...[more]

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